Head and neck cancers affect 40,000 individuals each year, accounting for 6% of malignancies. Radiation therapy, a mainstay of treatment, often causes irreversible damage to the salivary glands resulting in permanent xerostomia or dry mouth. These patients are at risk for oral and systemic infection and also experience significantly diminished quality of life. Our current treatments are only palliative (e.g. artificil saliva / chewing gum) and do not address the underlying pathology. Recent results from our laboratory have demonstrated therapeutic efficacy of nanoparticle (NP) mediated siRNA delivery to irradiated salivary tissue in a preclinical murine model. This transiently modulates th cellular response to radiation to favor survival. What remains unclear, however, is long term viability of this and other radioprotective strategies, particularly in evaluating the potential fo cellular quiescence or the risk of secondary malignancy. To investigate long term fate of radioprotected tissue, a needed step towards clinical translation, we are developing a nanoparticle system to co-deliver siRNA and an active estrogen agonist (Aim 1). This agent, 4-hydroxytamoxifen (4-OHT), when delivered to the appropriate transgenic tissues, will induce expression of a fluorescent reporter protein that will persist in treated cells and daughter cells beyond the transient effect of siRNA. Additionally, because the majority of radiation damage to biological tissues is from reactive oxygen species (ROS), we are interested in dampening the initial radiation insult. The only FDA-approved xerostomia prophylactic agent is amifostine, an intravenously administered radical scavenger, with a narrow therapeutic window, and the potential for systemic side effects including tumor protection. Our proposed strategy is to locally pre-treat the gland with a novel nanoparticle formulation aimed at arming salivary tissues with an antioxidant supply via the sustained intracellular release of active amifostine (Aim 2). Completion of these aims will identify targets and sequellae of radioprotection, while simultaneously determining which of the two therapeutic strategies is more effective. Also detailed within this application are clinical activities to complement the research training of the applicant. Both sponsors are committed to the applicant's development as a clinician-scientist and will continue to train the applicant in experimental design, scientific writing, and presentation. The applicant will also pursue four longitudinal clinical experiences with physicians working in cancer treatment to gain a better understanding of the clinical context of his research. Finally, the applicant will continue involvement in the development of future experimental studies during his medical training.